Novel Stilbene-Based Antileukemic Agents Active in P-Glycoprotein Expressing and Apoptosis-Resistant Acute Leukaemia Cell Lines.

The stilbene scaffold is a basic element for a number of biologically active natural and synthetic compounds and in accordance with Evans’ definition it can be considered as a privileged structure. One of the most relevant and studied stilbenes is Resveratrol, a phytoalexin present in grapes, endowed with chemopreventive and chemotherapeutic properties and able to induce apoptosis in different cancer cell lines. Since reduced apoptosis has been implicated in the development and progression of malignant tumors and in the occurrence of chemoresistant phenotypes, resveratrol-induced apoptosis might therefore contribute to its antitumor activity. However, resveratrol is a not potent cytotoxic compound if compared with others chemotherapeutic drugs and it is scarcely active in P-glycoprotein expressing (MDR) and Bcr-Abl expressing leukaemia cells. With the aim to find new stilbene compounds active in resistant leukaemia cells we synthesized a small library of resveratrol analogs, bearing the 3,5-dimethoxy motif at the A phenyl ring and amino, methoxy and hydroxy moieties at the 3′-and/or 4′-positions. Moreover, we synthesized analogues which incorporate a phenyl ring as bioisosteric substitution of the alkenyl bridge. Among these new stilbenes we identified two compounds endowed with interesting antileukemic properties: a) a methoxylated cis derivative active at nanomolar concentrations in P-glycoprotein expressing HL60-R and CEM VBL100 acute leukaemia cell lines and in P-glycoprotein and Bcr-Abl expressing K562-ADR cell line which is resistant to apoptosis induced by most common anticancer agents, and b) a terphenyl derivative active in MDR and Bcr-Abl expressing cell lines. Both compounds induced apoptosis prevalently through the mitochondrial pathway. Differently from resveratrol and other stilbenes, the therphenyl derivative induced a block of cells in G0-G1 phase of cell cycle which was associated to the shift of the phosphorylation state of pRb from hyperphosphorylated to hypophosphorylated. Morover, low concentrations of this compound were able to induced a potent granulocytic and monocytic differentiation of HL60 cells.